Slip preference analysis (SPA) is accomplished by examining fault activation driven by different Andersonian strike-slip stress regimes. Strike-slip regimes favour the activation of strike-slip faults striking as high as 45° from the trend of the σ1 axis, thus favouring the predominance of R shears over P shears in a strike-slip shear zone. Reverse and normal faults cannot be activated simultaneously by a common strike-slip stress regime, and their activations depend on the stress ratio. The SPA provides new constraints on stress inversion methods that take into account only the misfit angle minimization criteria. Insights from the SPA give rise to an alternative explanation of the origin of the Tertiary Rhodope metamorphic core complex exposed in the inner part of the Hellenic orogen, which attributes the activation of the associated extensional shear zones and detachments to an Andersonian, transpression–strike-slip (TRP–SS) to strike-slip (SS) stress regime, and not to an extensional one as widely assumed. The variation from TRP–SS to SS is critical for the activation of the extensional structures and is attributed to the local and at-depth increase of the vertical crustal stresses owing to the ascent and emplacement of large plutonic bodies.